1. Field of the Invention
This invention relates to substantially anhydrous pharmacologically active agents which are protectively microencapsulated within proteinoid microspheres and to their preparation. It relates particularly to the oral administration of dehydrated microspheres encapsulating biologically active agents, such as polypeptides, which otherwise would be labile in storage and poorly absorbed from the gastrointestinal tract.
2. Description of the Prior Art
The available modes of delivery of pharmaceutical and therapeutic agents often are severely limited by chemical or physical barriers or both, which are imposed by the body. For example, oral delivery of many such agents would be the general method of choice if not for the numerous barriers faced by these agents along this route. Gastrointestinal conditions of inappropriate pH, the presence of powerful digestive enzymes, the permeability properties of gastrointestinal membranes and tissues and other factors all play important roles in determining the feasibility of oral delivery of active agents to their targets. Among the numerous pharmacological agents which are known to be adversely affected or rendered ineffective when administered orally are the biologically active polypeptides and proteins, such as insulin, and mucopolysaccharides, such as heparin. These agents are rapidly destroyed in the stomach by acid hydrolysis and in the stomach and lower gastrointestinal tract by enzymes and, in addition, they pass poorly, if at all, through the gastrointestinal mucosa.
A great deal of effort has been concentrated on the modification or isolation of the deleterious conditions within the gastrointestinal tract so that a pharmacological agent, which otherwise would be labile, could be absorbed through the stomach or intestine wall intact and in pharmacologically active form.
Copending application Ser. No. 98,027 issued as U.S. Pat. No. 4,925,673, the disclosure of which is incorporated herein by reference, teaches that hollow acidic, basic and neutral proteinoid microspheres form spontaneously in and encapsulate acidic, basic and neutral aqueous environments, respectively, and, being stable in those environments, effectively isolate and protect a pharmacological agent encapsulated therein. It also teaches that the agent can be quickly released in pharmacologically active form merely by a change in pH which causes the microspheres to lose their protective structural integrity and that such microspheres that have a diameter of less than about 10 microns readily penetrate the gastrointestinal mucosa.
More specifically, application Ser. No. 98.027 issued as U.S. Pat. No. 4,925,673 teaches that contacting an acidic proteinoid with an acidic aqueous solution or suspension of a pharmacological agent which is stable in such solution or suspension results in the spontaneous formation of hollow proteinoid microspheres encapsulating the pharmacological agent. These microspheres, being stable to stomach acids and enzymes, protect an encapsulated pharmacological agent from those acids and enzymes. Such microspheres having a diameter of less than about 10 microns readily penetrate the gastrointestinal mucosa and enter a higher pH environment where the acidic proteinoid capsule material is unstable and releases the pharmacological agent in physiologically active form into the near neutral blood stream.
It also teaches how to encapsulate within basic proteinoid microspheres pharmacological agents which are sensitive to the conditions of encapsulation within acidic proteinoid microspheres. Such microcapsules form spontaneously when the basic proteinoid is contacted with a basic aqueous solution or suspension of that pharmacological agent. The resulting microspheres are stable in the mildly basic portions of the lower digestive tract, thereby protecting the encapsulated agent from intestinal enzymes. As in the case of the acidic microspheres, basic proteinoid microspheres having a diameter of less than about 10 microns will readily penetrate the gastrointestinal mucosa into a lower pH environment where the capsule material is unstable and releases the active pharmacological agent in the near neutral blood.
Ser. No. 98.027 issued as U.S. Pat. No. 4,925,673 further teaches how to encapsulate a pharmacological agent within neutral proteinoid microspheres by contacting neutral proteinoid with a neutral aqueous solution or suspension of that agent. Such microspheres are stable in the near neutral bloodstream and release the active agent in response to higher or lower pH at which these microspheres are unstable.
Ser. No. 98,027 issued as U.S. Pat. No. 4,925,673 thus provides an effective means for targeting the release of a pharmacologically active agent in an animal by incorporating same in proteinoid microspheres which are stable to the conditions encountered during migration from the point of introduction into the animal to a targeted release zone where they are unstable. However, the water content of such microspheres often leads to an undesirably short shelf life or storage stability.
Since the microspheres can be punctured by the large ice crystals which form during natural freezing, it is essential that they be protected from such conditions during both shipment and storage. In addition, the presence of water in contact with many pharmacological agents results in the progressive hydrolysis of chemical bonds and degradation of the biological activity. In the case of insulin and other biologically active polypeptides, this degradation is quite rapid. For example, although Ser. No. 98,027 issued as U.S. Pat. No. 4,925,673 shows that the unrefrigerated shelf life of aqueous insulin can be dramatically lengthened by encapsulation within acidic proteinoid microspheres, that shelf life is measured only in weeks. Still another problem is introduced by the fact that it is exceedingly difficult to isolate the microspheres from a wide variety of microorganisms, including certain molds having air borne spores, which are capable, in a aqueous environment, of utilizing the proteinoid as a nutrient. Such microorganisms also can similarly attack and destroy insulin, as well as other polypeptides, proteins and certain polysaccharides.
Since dehydration has long been known to enhance the shelf life of many unencapsulated pharmacological agents, including insulin (the effectiveness of which can be extended for several months), efforts have been made to dehydrate orally administerable acidic proteinoid microspheres containing aqueous insulin by vacuum drying at room or slightly elevated temperatures. Although this procedure dehydrates the insulin, the pressure drop across the proteinoid capsular walls resulting from the egress of liquid water ruptures those walls and exposes the dehydrated insulin, thereby rendering the composition unsuited for oral administration.